Impairments of oxidative/energy metabolism are characteristic of Alzheimer's Disease (AD) and also occur in CAGn/Qn expansion diseases. In AD, the Krebs cycle component KGDHC is deficient. In this revised Program Project, the mechanisms of the impairments of energy/oxidative metabolism will be clarified and compared in AD and in the expansion disorders. Project 1 will elucidate the abnormalities in the constituent proteins of KGDHC which are responsible for its deficiency in AD. New data since the previous review suggest an association of a subgroup of familial AD with polymorphisms in a gene (DLST) for a KGDHC constituent; the basis of this apparent association will also be elucidate. Project 2 will determine the effects of decreasing KGDHC activity in isolated mitochondria on oxidative stress, calcium metabolism, the permeability transition, and mtDNA transcription Project 3 focuses on determining whether conditions known to cause neurodegeneration (e.g. oxidative stress, calcium balance) impair KGDHC in intact, cultured cells, and if so whether such impairment contributes to cell death or to the development of other changes associated with neurodegeneration. Project 4 will determine the role of transglutaminase (Tgase)-mediated reactions in the CAGn/Qn diseases. This project has been extensively revised because of findings since the last review. These include demonstration that in vitro, Tgase covalently links Qn expansions to KGDHC as well as to GAPDH. Tgase action on histone aggregates them. TGase activity is reportedly increased in AD brain, and has been proposed to play a role in the formation of insoluble aggregates in both AD and CAGn/Qn disorders. Project 5 is a new project. It will utilize a number of transgenic mouse models to elucidate mechanisms in both AD and the CAGn/Qn disorders, including a newly available mouse heterozygous for deficiency of a component of KGDHC (Dld+/-). Dr. M. Flint Beal, who is joining the Cornell faculty as of July 1998 (as chair of Neurology and Neuroscience), will direct Project 5. An Administrative Core will support of the projects and a Tissue Culture Core will support at least 3 of the projects. Interactions among the Projects will be close. These studies will clarify further the role of abnormalities in energy/oxidative metabolism in AD and in the CAGn/Qn disorders, including whether or not the deficiency of KGDHC is important in the pathophysiology of AD.